Abstract: Novel therapies to prevent and reverse adverse immune responses are needed in allergy, autoimmunity, and monogenic diseases. The focus of our lab is to develop and translate effective therapies to prevent and reverse such adverse immune responses. For example, allergies to food, venom or pollen affect up to one in five Americans but treatments primarily involve provision of systemic symptomatic relief and very few offer direct efforts to prevent or reverse the specific responsiveness. The long-term goal of this project is to develop a therapeutic approach that safely confers long-lasting protection against allergic disease in an antigen-specific manner. Regulatory T-cell (Treg) therapy is potentially promising, but polyclonal Tregs are not specific. Our lab has developed engineered human and mouse regulatory T cells (Tregs), rendered specific by expression of single chain Fv or T-cell receptors (TCR) as chimeric antigen receptors (CAR), both of which have shown efficacy in vitro and in vivo in models of hemophilia and autoimmunity. Recently, we modified this Treg approach to express antigen on Tregs; these cells, which we term BAR (for B-cell Antibody Receptor Tregs), can interact and suppress specific B cells via recognition by the B-cell receptor, an approach that has long-term advantages over non-specific immune modulators or other CAR approaches. Importantly, BAR Tregs can suppress reactivity in a passive anaphylaxis model, a result that suggests direct activity of IgE-sensitized mast cells. We hypothesize that BAR Tregs have potential to treat allergy. In this proposal, we wish to focus on BAR Tregs because they target the relevant specific B cells or IgE-sensitized mast cells. Based on our preliminary data that both human and murine BAR Tregs are functional in a model of allergy to ovalbumin (OVA), our goals are to utilize these BAR Tregs in both active and passive anaphylaxis models to establish their effect on the IgE response and to follow their trafficking and persistence, as well as mechanism of action via targeting of IgE-sensitized mast cells. The results of this study would provide pre-clinical evidence for efficacy leading to clinical translation of adverse immune responses.